DESCRIPTION (Applicant's Description): The long-term goal of this project is to develop a computer modeling approach for the accurate prediction of dosimetry for cancer chemotherapy combination protocols in target tissues to achieve maximal therapeutic efficacy with minimal side effects. This proposal fits into the candidate's career development by providing an opportunity to incorporate physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling expertise into his background of biochemical and molecular pharmacology. The combined use of computer modeling approaches and animal experimentation will allow Dr. Gustafson to conduct more timely and innovative research in the fields of pharmacology and toxicology in relation to cancer. A Howard Temin Award would support Daniel L. Gustafson in the achievement of his long-term goal of having a successful career in academic science. Furthermore, this approach has the potential benefit of incorporating the physiological and disease states of individual patients into the computer modeling process for the "custom design" of the best therapeutic regimen for each patient. Development of this type of approach has a great deal of potential in both clinical and basic research. The proposed research integrates: a) PBPK/PD modeling; b) toxicology of chemical mixtures and toxicologic interactions; and c) animal/human models of cancer using athymic "nude" mice with human MX-1 mammary tumor xenografts. The work on these PBPK/PD models for individual drugs and drug mixtures will proceed as follows: 1) build PBPK/PD models for doxorubicin (DOX), cyclophosphamide (CP), methotrexate (MTX) and 5-fluorouracil (5-FU), singly and in combination, in BALB/c mice; 2) study pharmacokinetics thoroughly on DOX, CP, MTX and 5-FU, singly and in combination, in BALB/c mice and validate the PBPK models; 3) study pharmacodynamics of DOX, CP, MTX and 5-FU, singly and in combination, in athymic "nude" mice with human MX-1 mammary tumor xenografts, validate the PD models, and evaluate therapeutic efficacy; 4) build PBPK/PD models for DOX, CP, MTX and 5-FU, singly and in combination, in humans based on literature information and interspecies scaling from BALB/c mouse PBPK/PD models; and 5) validate human models using literature information.